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K.Y. Yoneda
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MINI 14 - Pre-Clinical Therapy (ID 119)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Fernandez-Cuesta, A.F. Gazdar
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI14.06 - High-Affinity α3β1 Integrin Ligand LXY30 for the Screening, Imaging and Targeted Drug Delivery in Non-Small Cell Lung Cancer (NSCLC) (ID 1758)
11:15 - 11:20 | Author(s): K.Y. Yoneda
- Abstract
- Presentation
Background:
High-affinity peptidomimetic or small-molecule ligands against cancer cell surface receptors have attracted wide interest as cancer-targeting agents to enhance cancer diagnosis and treatment. We have previously identified and characterized several peptide ligands specific for different integrins, such as a3b1, a4b1 and avb3, on live tumor cells using our invented high throughput one-bead one-compound (OBOC) random combinatorial libraries and “on-bead” whole-cell binding assay. The objective of this study was to select the best integrin ligand for the screening, imaging and targeted drug delivery studies in NSCLC.
Methods:
High-affinity integrin ligands coated on the surface of TentaGel resin beads were screened for the binding to a panel of NSCLC cell lines, malignant pleural effusion and peripheral blood mononuclear cells (PBMCs) from lung cancer patients using the established whole-cell binding assay. The binding affinity was determined in selected NSCLC tumors by flow cytometry using the biotinylated integrin ligands and Streptavidin-Phycoerythrin (PE). For in vivo biodistribution, mice bearing subcutaneous and intracranial NSCLC xenograft tumors were injected with LXY30-biotin-streptavidin-Cy5.5 conjugate for 6 hrs before being subjected to in vivo and ex vivo optical imaging.
Results:
Among the available integrin ligands, LXY30, a recently optimized cyclic peptide targeting α3β1integrin, bound to the majority of NSCLC cell lines tested within one hour of incubation. We further demonstrated that LXY30 bound to α3β1 integrin on the surface of lung cancer cells with high specificity by flow cytometry and entered into the cells via endocytosis by fluorescence microscopy imaging. Flow cytometry confirmed the high specificity binding of LXY30 to NSCLC cells. While sparing the PBMCs isolated from lung cancer patients, LXY30 strongly bound to tumor cells in the pleural effusion from several NSCLC patients and could capture the tumor cells spiked into PBMCs in 1: 5,000 dilution after a 2-hour incubation. Furthermore, several EGFR-mutant lung cancer cell lines have high level expression of α3β1 integrin on their surface. In nude mice bearing two representative, EGFR-mutant lung cancer H3255 (EGFR L858R) and H1975 (EGFR 858R/T790M) xenograft tumors, optical images have shown the preferential updates of LXY30-biotin-streptavidin-Cy5.5 conjugate in the subcutaneous and intracranial xenograft tumors.
Conclusion:
The rapid, sensitive and high specificity binding of LXY30 makes it an ideal candidate for screening and isolating NSCLC tumor cells in the pleural effusion and whole blood. LXY30 can be used as a cancer-targeting agent to guide in vivo delivery of imaging dye and cancer drugs to the simulated extracranial and metastatic brain tumors.
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MINI 31 - ALK (ID 158)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Malik, I. Ou
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 1a-1f
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MINI31.06 - Crizotinib and Interstitial Lung Disease: Systematic Review of Four Clinical Trials (ID 1580)
19:00 - 19:05 | Author(s): K.Y. Yoneda
- Abstract
- Presentation
Background:
Tyrosine kinase inhibitors (TKIs) have been associated with the development of a rare but serious and potentially fatal lung injury syndrome referred to as drug-induced interstitial lung disease (ILD). This has been best characterized for the epidermal growth factor receptor (EGFR) TKIs, with a typical presentation of delayed but rapidly progressive dyspnea leading to respiratory failure and death in up to one third of cases. While case reports of crizotinib-associated ILD have been published, little is known regarding the incidence, clinical characteristics, and mortality of crizotinib-associated ILD. In an effort to better understand this adverse event (AE), we performed a systematic review of respiratory-related events in the four largest clinical trials with crizotinib.
Methods:
An independent three-person panel composed of a pulmonologist, radiologist, and oncologist, none of whom were associated with any of the clinical studies, was convened to analyze respiratory AEs of grade ≥3 and any-grade AEs reported by the investigator as pneumonitis, ILD, or radiation pneumonitis in four crizotinib studies (PROFILE 1001, 1005, 1007, and 1014). After review by each panel member individually followed by consensus review, the events were classified either as disease progression or true respiratory AEs. Respiratory AEs were then further sub-classified as due to: 1) de novo ILD, 2) exacerbation or recurrence of pre-existing ILD, 3) concurrent illness (recurrence or progression of pre-existing condition), or 4) other toxicity not thought to be related to ILD (e.g. bacterial pneumonia).
Results:
There were a total of 1,669 patients in the four studies, among whom 446 events in 368 patients met the criteria for further analysis. Of these 446 events, 77 were attributed to progressive disease, 310 to other toxicity not thought related to ILD, 20 to de-novo ILD, 9 to concurrent illness, and 3 to exacerbation of underlying ILD. 27 cases (25 patients) were felt to have insufficient data to draw firm conclusions. Overall, the incidence of crizotinib-associated ILD was 1.2% (20/1,644) across the four studies, with no difference in incidence seen between Asian and Caucasian populations. The mean onset of ILD was 82 days. The mortality rate for patients identified with crizotinib-associated ILD was 50% (10/20). There was a trend towards improved survival if crizotinib was stopped rather than continued on presentation (64% [9/14] vs. 17% [1/6], P=0.065). Early administration of systemic corticosteroids did not seem to affect survival.
Conclusion:
This report represents the largest systematic review of TKI-associated ILD that has been performed by an independent multidisciplinary review panel. Crizotinib-associated ILD occurred in approximately 1.2% of patients who were administered crizotinib and displayed a characteristic pattern of delayed but rapidly progressive dyspnea and hypoxemia with a mortality of 50% (10/20). This pattern is similar to that seen with the EGFR TKIs, but appears to have a more delayed onset and a higher mortality rate. In contrast to EGFR TKI-associated ILD, which has a markedly higher incidence in the Asian population, there appears to be no such predilection for crizotinib-induced ILD. Immediate cessation of crizotinib may improve survival.
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